Ki-67 staining is a strong predictor of distant metastasis and mortality for men with prostate cancer treated with radiotherapy plus androgen deprivation: Radiation Therapy Oncology Group Trial 92-02.

PURPOSE: The Ki-67 staining index (Ki67-SI) has been associated with prostate cancer patient outcome; however, few studies have involved radiotherapy (RT) -treated patients. The association of Ki67-SI to local failure (LF), biochemical failure (BF), distant metastasis (DM), cause-specific death (CSD) and overall death (OD) was determined in men randomly assigned to short term androgen deprivation (STAD) + RT or long-term androgen deprivation (LTAD) + RT. PATIENTS AND METHODS: There were 537 patients (35.5%) on Radiation Therapy Oncology Group (RTOG) 92-02 who had sufficient tissue for Ki67-SI analysis. Median follow-up was 96.3 months. Ki67-SI cut points of 3.5% and 7.1% were previously found to be related to patient outcome and were examined here in a Cox proportional hazards multivariate analysis (MVA). Ki67-SI was also tested as a continuous variable. Covariates were dichotomized in accordance with stratification and randomization criteria. RESULTS: Median Ki67-SI was 6.5% (range, 0% to 58.2%). There was no difference in the distribution of patients in the Ki-67 analysis cohort (n = 537) and the other patients in RTOG 92-02 (n = 977) by any of the covariates or end points tested. In MVAs, Ki67-SI (continuous) was associated with LF (P =.08), BF (P =.0445), DM (P <.0001), CSD (P <.0001), and OD (P =.0094). When categoric variables were used in MVAs, the 3.5% Ki67-SI cut point was not significant. The 7.1% cut point was related to BF (P =.09), DM (P =.0008), and CSD (P =.017). Ki67-SI was the most significant correlate of DM and CSD. A detailed analysis of the hazard rates for DM in all possible covariate combinations revealed subgroups of patients treated with STAD + RT that did not require LTAD. CONCLUSION: Ki67-SI was the most significant determinant of DM and CSD and was also associated with OD. The Ki67-SI should be considered for the stratification of patients in future trials.

Loss of the short arm of the Y chromosome in human prostate carcinoma.

A change in Y chromosome number is one of the many cytogenetic abnormalities reported in human prostate tumors. However, reports in the literature have varied regarding the frequency of Y loss or gain and the significance of Y aneusomy with respect to the biology of the disease. We have conducted an analysis of the Y chromosome in malignant and benign hyperplastic human prostate epithelium in order to determine whether regional Y loss occurs in prostate cancer. To accomplish this we performed dual-color fluorescence in situ hybridization (FISH) on serial sections of paraffin-embedded prostate tumor tissues using either a Yp (SRY), Ycen (alpha-satellite) or Yq (satellite 3) probe, and an Xcen (alpha-satellite) probe that served as a control for hybridization and nuclear truncation. The results of our FISH analysis demonstrated loss of Yp in the malignant epithelium of 14/40 (35%) prostate tumor sections examined. We also found loss of Yq in 4/40 (10%) of the samples, with one of these exhibiting accompanying Yp loss. The remaining samples, 23/40 (58%), retained both Yp and Yq markers, with no evidence of either Ycen loss or Y gain in any of the tumor samples examined. In addition, Y loss was detected in the benign hyperplastic regions in nearly one-half of the tissue sections that exhibited Y loss in the malignant epithelium. These results demonstrate that regional chromosome Y loss occurs in prostate cancer, that loss of Yp is the most frequent event, and suggest that this loss may in some cases be a precursor to prostate malignancy.

Is there a subset of patients with PSA > or = 20 ng/ml who do well after conformal beam radiotherapy?

To determine if there is a subgroup of patients with pretreatment PSA > or = 20 ng/ml with a favorable outcome after external beam radiation therapy. We analyzed retrospectively treatment outcomes of 129 patients with pretreatment PSA > or = 20 ng/ml treated in our department from 2/88-8/94. Median patient age was 70 years (range 51-89 years). Tumor stage was T1/T2ab in 68, T2c/T3 in 61 patients. Initial Gleason grade was < 7 in 82 and > or = 7 in 47 patients. Median PSA was 35 ng/ml (mean 45 ng/ml, range 20-191 ng/ml). Ninety-seven patients received four-field conformal external beam radiation therapy. No patient received surgery or hormonal therapy prior to treatment. Median central axis dose was 73 Gy (range 68-79 Gy). Covariates considered in univariate and multivariate analyses included central axis dose, pretreatment PSA, presence of perineural invasion, Gleason score, palpable tumor stage and patient age. bNED failure was defined as a PSA > or = 1.5 and rising on two consecutive determinations. Median follow up was 50 months (range 3-100 months). Overall bNED control for the entire patient population was 22% at five years. Of the covariates analyzed, dose (P < 0.01), stage (P < 0.01), Gleason Score (P < 0.01), and the presence of PNI (P = 0.01) were significant on multivariate analysis. Based on these results, patients could be stratified into two distinct groups. Group I consisted of 19 patients with favorable features including T1/T2ab disease, Gleason Score 2-6, no perineural invasion treated to a dose > 73 Gy to the central axis. Patients in Group II had at least one of the above poor prognostic features or were treated to central axis doses < 73 Gy. The bNED control was significantly higher for patients in Group I than those in Group II (58% vs. 23%, P = 0.0027). There appears to be a favorable subgroup of patients with PSA > or = 20 ng/ml where treating to doses over 73 Gy to the central axis is warranted (four-year bNED rate of 58%). However, because of the small patient numbers, these results will need to be validated with longer follow up.

Utilization of fine-needle aspiration cytology and flow cytometry in the diagnosis and subclassification of primary and recurrent lymphoma.

BACKGROUND: The primary diagnosis of non-Hodgkin's lymphoma/leukemia (NHL) by fine-needle aspiration (FNA) is controversial. The authors reviewed their experience with FNA and flow cytometry (FC) to determine the usefulness and limitations of these techniques in the diagnosis of NHL. METHODS: Slides and reports from all lymph node and extranodal FNAs performed during the period July 1993 to January 1997 with a diagnosis of lymphoma or benign lymphoid process were reviewed. Clinical and biopsy follow-up data were recorded. Results were tabulated and the usefulness of cytology was analyzed. RESULTS: There were 100 adequate aspirates from 87 patients. These included 72 cases of NHL, 58 (80%) of which were diagnosed by FNA and FC without the need for histologic sampling (69% of the primary lymphomas and 88% of the recurrent lymphomas). There were 22 aspirates suspicious for lymphoma, 12 equivocal results, and 7 benign diagnoses. Eighty-six percent of malignant FNAs (50 of 58) had flow cytometry (FC) as compared with only 15% (5 of 34) of the suspicious or equivocal FNAs. CONCLUSIONS: FNA is a valuable method for diagnosing and subclassifying NHL, although immunophenotyping by FC is often an essential ancillary test. In our experience, correlating the FNA results with the FC results can eliminate the need for a more invasive surgical biopsy in many cases.

Histopathologic review of prostate biopsies from patients referred to a comprehensive cancer center: correlation of pathologic findings, analysis of cost, and impact on treatment.

BACKGROUND: Clinicians at the Fox Chase Cancer Center (FCCC) base prostate carcinoma treatment decisions regarding need to treat, field size, total dose, and adjuvant hormonal therapy on known prognostic factors including clinical stage, Gleason score (GS), perineural invasion (PNI), and pretreatment prostate specific antigen levels. The pathology of every patient is reviewed at FCCC to confirm a diagnosis of malignancy. The objective of this study was to define differences between pathologic reviews and their impact on treatment between outside institutions and FCCC. METHODS: The authors reviewed 538 pathology reports of prostate biopsies performed at both outside pathology departments and FCCC on patients evaluated between January 1993 and December 1996. The outside pathology reviews represented 107 community hospitals, academic institutions, and private pathology laboratories. Patients who had received hormonal therapy, cryosurgery, or radical prostatectomy prior to prostate biopsy were excluded from analysis. Final FCCC pathology determinations were compared with pathology reports from outside institutions. Reports then were analyzed to determine whether differences in interpretation would have resulted in different treatment strategies. Differences in percentages according to institutional type were evaluated using the chi-square statistic. The cost was assessed and cost per change in treatment estimated. RESULTS: The 538 pathology reviews identified a nearly 40% change in GS and a 13% change in > or =2 GS between the FCCC pathology review and 107 outside academic institutions. The results of this study showed that 22% of community hospitals, 10% of private laboratories, and 8% of academic institutions demonstrated at least 2 GS changes compared with the FCCC pathology review (p = 0.001). There was no significant difference observed between types of institutions in the incidence of PNI. CONCLUSIONS: This analysis provides evidence of a significant difference in the pathologic reviews of prostate biopsies conducted at FCCC and outside pathology departments. There was a nearly 40% change in GS and a 13% change in > or =2 GS between the FCCC pathology review and 107 outside institutions. The second pathology review added approximately $104 per case for a total of $55,952 to review all 538 cases. Overall, the savings in health care dollars resulting from the second pathologic review totaled $12,997. This second review of outside pathology in prostate cancer appears to be justified based on the treatment changes and on cost.

The value of transformed lymphocyte count in subclassification of non-Hodgkin's lymphoma by fine-needle aspiration.

No established criteria exist for predicting lymphoma grade or transformation in cytologic material. We counted transformed lymphocytes in fine-needle aspiration (FNA) biopsy specimens to determine whether the percentage of these cells in the smear could predict the histologic grade, the biologic behavior, or both. The percentage of transformed lymphocytes out of total lymphoid cells was determined on Papanicolaou-stained smears. Afterward, a cytodiagnosis was based on clinical information available at the time of the FNA, cytomorphologic data, and flow cytometry data. Results were correlated with results of examination of the surgical biopsy specimen, clinical behavior of the lymphoma, or both. The percentage of transformed lymphocytes was 10% or less in all low-grade or indolent lymphomas. Aspirates with transformed lymphocyte counts of 20% or greater were aggressive lymphomas. We also report our experience in the diagnosis of non-Hodgkin's lymphoma by FNA using cytomorphologic examination and immunophenotyping by flow cytometry at a cancer referral hospital. This is a preliminary study, and larger series may help establish the ranges of transformed lymphocyte counts that correlate with the lymphoma subtype.

Evidence of increased failure in the treatment of prostate carcinoma patients who have perineural invasion treated with three-dimensional conformal radiation therapy.

BACKGROUND: The detection of perineural invasion (PNI) in the diagnostic transrectal biopsy of the prostate is associated with a 93% frequency of extracapsular disease extension in patients treated by prostatectomy for adenocarcinoma of the prostate. Extracapsular extension is associated with an inferior outcome compared with that of patients who have organ-confined disease. This study examined the association of PNI and treatment failure in a consecutive series of patients treated with three-dimensional conformal radiation therapy (3DCRT) alone. METHODS: The authors report actuarial biochemical no evidence of disease (bNED) survival rates for 484 consecutive patients with clinically localized prostate carcinoma diagnosed by transrectal needle biopsy who completed 3DCRT alone between May 1989 and December 1994. The median follow-up time was 28 months (range, 2-75 months), and the median dose to the center of the prostate was 7368 centigray (cGy) (range, 6316-8074 cGy). Patients were subdivided into 2 groups according to pretreatment prostate specific antigen (PSA) levels (< 20 ng/mL vs. > or = 20 ng/mL). Pathology records were reviewed for the presence or absence of PNI. bNED failure was defined as a PSA level > or = 1.5 ng/mL and rising on 2 consecutive occasions. bNED survival rates were calculated using Kaplan-Meier methodology and comparisons of survival curves were accomplished using the log rank test. RESULTS: The 3-year bNED survival for all 484 patients was 77%. The presence of PNI predicted decreased bNED survival in all patients. This detrimental effect, however, was confined to patients with pretreatment PSA values < 20 ng/mL. The bNED survival rates for patients with pretreatment PSA < 20 ng/mL demonstrated a highly significant decrease if PNI was present versus when it was absent (65% vs. 88% at 3 years, 39% vs. 65% at 5 years; P = 0.0009 for overall curve comparison). For patients with pretreatment PSA < 20 ng/mL, multivariate analysis of prognostic variables demonstrated a significant association between bNED survival and PNI (P = 0.002), palpation stage (P = 0.02), and pretreatment PSA (P = 0.006). Gleason score, age, and dose were not independent predictors of bNED survival in this group of patients. CONCLUSIONS: To the authors' knowledge, this is the first report demonstrating that PNI detected on diagnostic transrectal biopsy is a significant predictor of decreased bNED survival in patients treated with radiotherapy. The subgroup of patients affected are those with pretreatment PSA < 20 ng/mL. This result suggests that such patients may benefit from more aggressive treatment, particularly the use of larger planning target volumes or adjuvant therapies.

Radiation therapy as treatment for stage T1c prostate cancers.

Preliminary outcomes are reported for 202 patients with T1c prostate cancer treated with three-dimensional conformal radiation treatment (3DCRT). At 5 years, actuarial freedom from failure is demonstrated in 97% of patients with pretreatment PSA levels of < 10 ng/ml, in 88% of those with PSA levels of 10-19.9 ng/ml, and in 91% of young patients (< or = 65 years) with PSA levels of < 20 ng/ml. The late morbidity following this technology is extremely favorable, with < 1% of patients developing serious GI sequelae, < 1% using a daily pad for incontinence, and 61% maintaining sexual potency. Continued development and use of 3DCRT technology is indicated for patients who elect external beam radiation treatment.

Evidence of acquired immune deficiencies in Mediterranean lymphoma. A possible aetiological link.

Patients with Mediterranean lymphoma (M.L.) had a significant reduction in humoral immunity (IgG and IgM) as well as impaired cellular immunity (50% were anergic to three antigens--P.P.D., mumps, and dinitrochlorobenzene). Any hypothesis for the pathogenesis of M.L. has to account for the peculiar geographic distribution of the disease, the age and sex incidence, the plasma-cell nature of the tumours, the associated heavy plasmacytic proliferation with relatively intact intestinal mucosa, involvement of the proximal small intestine, and alpha-chain production in a large proportion of patients. All areas in which M.L. is common are currently involved in the seventh cholera pandemic. Vibrio cholerae toxin inhibits both immediate and delayed immune reaction in vitro through its effect on cyclic adenosine monophosphate. V. cholerae antigens stimulate the proliferation of IgA-producing immunocytes in the mucosa without deeply penetrating the mucosa. The proximal small bowel is usually affected by the disease but there is little epithelial damage. The population in endemic areas is continuously exposed to V. cholerae antigens and toxins. It is suggested that such exposure, under certain genetic or other circumstances, may produce a state of immunosuppression in the gut thus accelerating, predisposing to, or producing lymphoplasmacytic neoplasia.